Lipids as ligands of nuclear receptor mediated gene expression

Abstract

The liver X receptors (LXRalpha and LXRbeta) are members of the nuclear hormone receptor family of ligand‐activated transcription factors. LXRs have been identified as cellular sterol sensors that are activated by cholesterol‐derived oxysterols to increase the expression of genes that contribute to cholesterol catabolism, efflux and elimination. These qualities make the LXRs attractive therapeutic targets for intervention in atherosclerosis. The majority of studies defining the actions of LXRs have been performed in the mouse model, taking advantage of genetically modified mouse strains devoid of LXRs. When an LXRalpha‐null mouse is fed dietary cholesterol, it fails to increase the expression of LXR target genes and consequently accumulates plasma and hepatic cholesterol and shows no increase in plasma and liver triglycerides. Interestingly, the Golden Syrian hamster also shows this dietary cholesterol‐induced phenotype, and fails to exhibit upregulation of hepatic LXR target genes such as CYP7A1 and SREBP‐1c. These observations prompted us to ask if the LXR‐signaling pathway is intact in the hamster, and whether we could use these qualities to further investigate LXR biology using the cholesterol‐fed hamster.We have cloned and characterized hamster LXRalpha, evaluated the promoter motifs of LXR target genes, and compared the effects of dietary cholesterol and synthetic LXR ligands on cholesterol homeostasis and hepatic gene regulation to define this differential response to dietary cholesterol in this valuable animal model.Supported by a grant from the American Heart Association (JJR)